Abstract

Disparities in cocaine-induced neurochemical and metabolic responses between human beings and rodents motivate the use of non-human primates (NHP) to model consequences of repeated cocaine exposure in human subjects. To characterize the functional response to cocaine infusion in NHP brain, we employed contrast-enhanced fMRI during both non-contingent injection of drug and self-administration of cocaine in the magnet. Cocaine robustly decreased cerebral blood volume (CBV) throughout basal ganglia and motor/pre-motor cortex and produced subtle functional inhibition of prefrontal cortex. No brain regions exhibited significant elevation of CBV in response to cocaine challenge. Theses effects in NHP brain are opposite in sign to the cocaine-induced fMRI response in rats, but consistent with previous measurements in NHP based on glucose metabolism. Because the striatal ratio of D2 to D1 receptors is larger in human beings and NHP than rats, we hypothesize that the inhibitory effects of D2 receptor binding dominate the functional response in primates, whereas excitatory D1 receptor stimulation predominates in the rat. If the NHP accurately models the human response to cocaine, downregulation of D2 receptors in human cocaine-abusing populations can be expected to blunt cocaine-induced functional responses, contributing to the weak and variable fMRI responses reported in human basal ganglia following cocaine infusion.

(a) Based on the measured non-contingent response to bolus infusion of 0.25 mg/kg cocaine (inset), the response to multiple microinjections can be predicted from a linear model during an extended period of cocaine availability (a) or periodic periods of drug availability and restriction (b). For simplicity, only half of the microinjections used to predict the total response are shown. Contingent infusion data (standard errors) from whole putamen are compared with predictions, which are the analysis regressors, based on the actual timing of infusions of 0.015 mg/kg cocaine in monkeys M1 (c) and M2 (d).

Non-contingent (a, b) and contingent (c, d) data. (a) The temporal response of whole putamen to bolus injection of 0.5 mg/kg cocaine in monkeys M1 and M2. (b) Percentage changes in CBV generated from the non-contingent infusion data. (c) Repeated measurements from whole putamen using cocaine self-administration. Each point indicates a result from one fMRI run, and groups of adjacent filled or open circles correspond to multiple runs within a single fMRI session. Lines represent the average response magnitude for each monkey after accounting for error bars. (d) The spatial pattern during self-administration produced from a random-effects analysis across all fMRI runs; note the fourfold smaller scale relative to the non-contingent map. Colored voxels in both maps passed a statistical threshold of p<0.05 after a correction for multiple comparisons. See online version for color information.

A spatial map of the peak magnitude of the cocaine-induced response averaged across animals, transposed onto a population-averaged rhesus brain (), and reported as a percentage change in CBV, with negative changes using the blue-green color scale and positive changes using the red-yellow scale. Slices cover basal ganglia from 9 to 20 mm anterior to ear bars in a stereotaxic coordinate space (). Highlighted regions include putamen (red lines), caudate (yellow), and nucleus accumbens (purple).

Functional activation in the frontal cortex measured as the percentage change in CBV (color scale) for regions that responded significantly by a random-effects analysis across fMRI sessions and monkeys. Activity is shown on right and left partially inflated hemispheres of the F99 cortical surface template (). Numerals indicate Brodmann areas based on macaque probabilistic atlases: black borders from ; green borders from . See online version for color information.

During two scanning periods separated by 3 months of cocaine abstinence and 3 months of reinstatement in one monkey, the negative response magnitude in one monkey (M1) became statistically smaller, as assessed by repeated measurements across magnet sessions.